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Hoffmann, R. A wiki for the life sciences where authorship matters. Nature Genetics (2008)

Involvement of peripheral-type benzodiazepine receptors in the proconvulsant actions of pyrethroid insecticides.

It has been demonstrated previously that select Type II pyrethroids are potent proconvulsants in the rat and that the proconvulsant actions of deltamethrin are blocked by administration of PK 11195, an antagonist of the peripheral-type benzodiazepine receptor (PTBR). The present investigation has extended these findings to include various Type I pyrethroids as proconvulsants. Additionally, the proconvulsant activity of cismethrin was reversed by administration of PK 11195. Pyrethroid displacement of specific [3H]Ro5-4864 binding to rat brain membranes was investigated to further define the interaction of pyrethroids with the PTBR. Both Type I and Type II pyrethroids potently inhibited [3H]Ro5-4864 binding with affinities ranging from nanomolar to micromolar. The ED50 values for the proconvulsant effects of both Type I and Type II pyrethroids were significantly correlated with their respective IC50 values as inhibitors of [3H]Ro5-4864 binding. [3H]Ro5-4864 saturation isotherms performed in the presence of fixed concentrations of deltamethrin or cismethrin showed that these pyrethroids increased the observed Kd values for [3H]Ro5-4864 with no change in the maximum number of binding sites. However, Schild plot analysis of the effect of deltamethrin on [3H]Ro5-4864 affinity was nonlinear with the Kd shift approaching a limiting value. Considered together these results suggest an allosteric effect of pyrethroids on [3H]Ro5-4864 binding, and provide additional support for the involvement of the PTBR in the proconvulsant actions of pyrethroids.[1]


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